Leishmaniasis comprises several diseases caused by intracellular protozoan parasites belonging to the genus Leishmania that mainly infect macrophages of a variety of mammals including humans and dogs. Depending largely on the species of the parasite and the immunocompetence state of the human host, the disease spectrum ranges from self-healing cutaneous leishmaniasis (CL) to fatal visceral leishmaniasis (VL) or kala-azar (18). Canine viscerocutaneous leishmaniasis (VCL) caused by Leishmania infantum and L. chagasi is an important emerging zoonosis found in countries around the Mediterranean basin, in the Middle East and in Latin America (16); being dogs the major reservoir of these parasites playing a central role in the transmission to humans by phebotomine sand flies (44). The outcome of infection is determined by interactions between the host immune system and the different parasite species, yet the pathogenesis of leishmaniasis remains unclear and the knowledge on the mechanisms involved in the immune response to Leishmania in humans and dogs is still limited.
Generally, protective immunity is associated with a classical cell mediated immune response that induces macrophage activation by T-cell derived cytokines. On the other hand, non-healing disease is associated with the generation of strong humoral responses (15, 24).
Research for the development of second generation vaccines, based on crude parasite fractions or on defined parasite antigens, was addressed to the identification of different surface or secreted parasite molecules that have been tested as vaccine candidates in several experimental models using diverse adjuvants (1, 17, 20, 43, 45, 46, 49, 50). The screening of expression libraries with sera from infected animals or humans has also enabled the selection of a few antigens as candidate vaccines (reviewed in (9)). Among them, those that elicit primarily a Th1-type immune response in infected mice or human patient cells, irrespective of their cellular location, have been implicated in the generation of protective responses in different animal models (48, 51, 52). On the other hand, some of the isolated antigens are intracellular conserved proteins that predominantly stimulate humoral responses in humans or dogs suffering VL or Th2-mediated humoral responses in experimentally infected mice (3, 33, 35, 37, 39). The inadequate humoral response induced against them in dogs suffering from leishmaniasis is thought to result in immunopathology, mainly due to the adverse effects of immune complexes such as uveitis (13), central nervous system lesions (14) or nephritis (21, 22, 30, 31). It has also been recently shown that the presence of IgG immune complexes in humans with VL correlates to an inability to resolve infections, demonstrating that immune complexes can be detrimental to the infected host (27). In spite of not being considered at first as good vaccine candidates, proteins that induce a high humoral response during the infectious process have been associated with the induction of a protective response. For example, parasite tubulins and the histone H2B were recognized by T-cell clones derived from an immune donor (36). In addition, rK39 causes proliferation and IFN-γ production by T cells from immune mice (23.) It has been also shown that genetic immunization with parasite H2B, H3 and H4 genes induces protection in murine visceral leishmaniasis models (62). Also, immunization of the receptor for activated C kinase (LACK) (29), some parasite cystein proteinases (38, 41) or the parasite nucleosome forming histones (11, 19) administered with Th1-promoting adjuvants generate immune responses that correlate to protection against cutaneous leishmaniasis in murine models.
Among the evolutionary conserved antigens of Leishmania, several lines of evidence suggest that ribosomal proteins are immunologically relevant molecules during Leishmania infection. In some cases, ribosomal constituents can contribute to the host immune system dysfunction through their capacity to modulate cell activities and cytokine release during infection. Thus, injection of the L. major ribosomal protein S3a into BALB/c mice induced the polyclonal expansion of B-cell clones and inhibited T-cell proliferation (10). Also, genetic immunization with a DNA vaccine coding for the putative 60S ribosomal protein L31 exacerbated the disease in mice models by the induction of IL-10 and Th2 cytokines (41, 63). In addition, some parasite ribosomal proteins like the parasite acidic P proteins have been related to the generation of strong humoral responses in dogs and humans suffering leishmaniasis (reviewed in (39)). However, it has also been shown that several ribosomal proteins tested were not able to induce an immunogenic protective response or, the immunogenic protective response obtained was sub-optimal (55, 41).
Despite all the attempts so far, there is still no valuable vaccines against a parasitic disease such as leishmaniasis. Therefore, there is still an important need for such a vaccine.